A crucial role for forebrain adenosine A2A receptors in amphetamine sensitization
A crucial role for forebrain adenosine A2A receptors in amphetamine sensitization
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DOI：
10.1038/sj.npp.1300630
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发表时间：
2005-05-01
影响因子：
7.6
通讯作者：
Schwarzschild, MA
中科院分区：
文献类型：
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作者：
Bastia, E;Xu, YH;Schwarzschild, MA
腺苷A（2A）受体（A（2A）Rs）在精神兴奋剂成瘾中影响对多巴胺能重复刺激的适应不良的CNS反应。A（2A）Rs在脑中的表达主要局限于丘脑核和纹状体，在那里分子适应介导精神兴奋剂的慢性效应，如行为敏化。利用一种新的前脑特异性条件性（Cre//oxP系统）敲除A（2A）R与经典的药理学方法相结合，我们研究了大脑A（2A）R参与安非他明诱导的行为敏化。通过放射自显影、PCR和A（2A）拮抗剂诱导的运动刺激的丧失证实了受体的组织特异性功能破坏。每天用安非他明治疗一周，在第8天显著增强对照小鼠的运动反应，并且在一周的洗脱后，致敏作用仍然很强。然而，它们的条件性基因敲除同窝仔在第8天未显示对苯丙胺的致敏性，并且在洗脱后仅显示适度的致敏性。腺苷A（2A）Rs的药理学阻断也能够阻断多种小鼠品系中致敏作用的发展（但不表达）。因此，大脑A（2A）Rs的激活在反复暴露于精神刺激剂后产生增强的精神刺激反应中起着关键作用。
Adenosine A(2A) receptors (A(2A)Rs) are well positioned to influence the maladaptive CNS responses to repeated dopaminergic stimulation in psychostimulant addiction. Expression of A(2A)Rs in brain is largely restricted to the nucleus accumbens and striatum, where molecular adaptations mediate chronic effects of psychostimulants such as behavioral sensitization. Using a novel forebrain-specific conditional (Cre//oxP system) knockout of the A(2A)R in coordination with classical pharmacological approaches, we investigated the involvement of brain A(2A)Rs in amphetamine-induced behavioral sensitization. Tissue-specific, functional disruption of the receptor was confirmed by autoradiography, PCR, and the loss of A(2A) antagonist-induced motor stimulation. Daily treatment with amphetamine for I week markedly enhanced locomotor responses on day 8 in control mice and the sensitization remained robust after a week of washout. Their conditional knockout littermates however showed no sensitization to amphetamine on day 8 and only a modest sensitization following the washout. Pharmacological blockade of adenosine A(2A)Rs also was able to block the development (but not the expression) of sensitization in multiple mouse strains. Thus activation of brain A(2A)Rs plays a critical role in developing augmented psychomotor responses to repeated psychostimulant exposure.